Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and increased risk of late-onset neurodegeneration. Surprisingly, we found microglia mutant clones associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the grey nuclei of the rhombencephalon, in patients with LCH and ECD whether or not they presented with clinical symptoms of neurodegeneration at the time of death. The presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003), indicating a phase of subclinical incipient neurodegeneration. Depletion of mutant microglia by a CSF1R-inhibitor in a mouse model of incipient disease limited neuronal loss and improved survival. Disease topography was attributable to a local proliferative advantage of mutant microglia. Genetic bar-coding analysis suggest that mutant clones originate from either definitive or yolk sac hematopoiesis depending on patients. These studies characterize a progressive neurodegenerative disease associated with clonal proliferation of inflammatory microglia (CPIM), and a preclinical stage of incipient disease which represents a therapeutic window for prevention of neuronal death.